Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model

Abstract

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease.

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

“…Involvement in AD pathology TNF-α TNF-α is involved in inducing acute phase inflammation and is elevated in AD serum, cerebrospinal fluid (CSF) and cortex (Tarkowski et al, 1999(Tarkowski et al, , 2003. Anti-TNF-α treatment reduces Aβ deposition, behavioral impairments, and inflammation in AD animal models suggesting TNF-α is detrimental factor in AD (Russo et al, 2012;Tweedie et al, 2012;Detrait et al, 2014;Gabbita et al, 2015). However, one study suggests that TNF-α expression in APP transgenic mice at early stage induces glial uptake of Aβ (Chakrabarty et al, 2011).…”

Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks

“…Further, TNF-α was described to induce APP mRNA expression in a dose-dependent manner via nuclear factor k B activation [ 82 ]. Consistently, TNF-α modulation decreased fibrillar amyloid accumulation [ 83 ] and chronic administration of TNF-α lowering agents decreased APP levels, soluble Aβ 1-42 and Aβ deposition in old 3xtg AD mice [ 84 ]. However, expression of murine TNF-α in APP tg mice at early stage rendered in attenuated Aβ 1-42 and Aβ 1-40 plaque burden and deposition, without difference in APP levels [ 85 ].…”

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…High levels of TNF-α have also been identified in murine models of AD that resemble the classical behavioral abnormalities of the disease in humans (Gabbita et al, 2012;Kinney et al, 2018). Blocking the TNF-α pathway decreases central immune infiltration and prevents AD neurochemical and behavioral phenotypes Prasad Gabbita et al, 2015), suggesting that central-peripheral cross-talk may be implicated in the disease. Notably, experimental studies using transgenic AD models have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) can reduce AD pathology (Kinney et al, 2018).…”